In vitro models have been developed to study the cellular and molecular mechanisms by which osseous metastases are formed in patients with breast cancer. We have found that human breast cancer cells resorb bone directly. We plan now to examine the molecular mechanism of breast cancer cell-mediated bone resorption, including the characterization of the factors released by cultured human breast cancer cells which resorb bone, determination of the relationship between mineral release and matrix resorption, and the roles of lysosomal enzymes and collagenase. We also plan to determine the mechanism of bone resorption in two rat breast tumor models associated with hypercalcemia. We plan to continue our studies on the bone-derived chemotactic factor for breast-cancer cells, including its biological and chemical characterization and identification of agents which inhibit it. We will also continue our studies on the role of prostaglandins in the hypercalcemia of malignancy and examine supernatants of cultured human breast cancer cell lines for factors which stimulate new bone formation.